Truvada PrEP Causes Only Minimal Bone Loss, Raltegravir Easier on Bones than PIs

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Use of tenofovir/emtricitabine (Truvada) for HIV pre-exposure prophylaxis (PrEP) was associated with a small decrease in bone mineral density that stabilized after the first 6 months, according to study findings reported in the April 23 edition of Clinical Infectious Diseases. Related research showed that HIV-positive people starting an antiretroviral regimen containing the integrase inhibitor raltegravir (Isentress) experienced less bone loss than those taking protease inhibitors.

Observational studies have found that people with HIV have an elevated risk of bone loss -- osteopenia or the more severe osteoporosis -- but it is not fully understood whether this is due to HIV infection itself, associated inflammatory and metabolic abnormalities, antiretroviral drug toxicity, or other factors.

Although the U.S. FDA approved Truvada for PrEP in 2012, tenofovir for HIV treatment (Viread, also in several antiretroviral single-tablet regimens) has been approved since 2001 and long-term data show that it is generally safe and well-tolerated. However, many HIV-positive people starting tenofovir-containing regimens experience a small amount of bone loss during the first few months of treatment, which then stabilizes. Data on the effects of tenofovir on bones in HIV-negative people is still needed.

Kathleen Mulligan from the University of California at San Francisco and colleagues looked at the effect of Truvada PrEP on bones in a subset of HIV-negative participants in the iPrEx study, usingdual-energy X-ray absorptiometry (DEXA) scans to assess bone mineral density (BMD).

The full iPrEx trial enrolled 2499 HIV-negative men who have sex with men (MSM) and transgender womenat 11 sites in North and South America, Africa, and Asia. Participants were generally young (average age 25 years), sexually active, and considered to be at high risk for HIV infection. They were randomly assigned to take either Truvada or placebo once-daily.The study showed that Truvada reduced the risk of HIV infection by 92% among those with detectable blood drug levels, with even greater protection for those with optimal adherence.

The bone substudy included 247 participants from the Truvada group and 251 from the placebo group. DEXA scans of the lumbar spine and hip were done at baseline and again at 24-week intervals for 2 years. At baseline, 12% were found to have pre-existing low spine bone density while 2% had low hip bone density.

Results

"In HIV-uninfected persons, [tenofovir/emtricitabine] PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with [tenofovir diphosphate], with more stable BMD thereafter," the study authors concluded.

They noted that these findings show that tenofovir-associated bone loss is independent of HIV infection or other antiretroviral drugs used concurrently by people with HIV. This small decrease in bone density does not appear to be associated with detrimental clinical outcomes such as fractures, and they suggested that the risk of Truvada for PrEP "is offset by the prevention of HIV infection, which requires combination antiretroviral therapy that is associated with relatively greater loss of BMD."

Nevertheless, they recommended that people interested in PrEP should be informed about the potential for bone loss and take steps to improve bone health, such as limiting use of alcohol and tobacco, increasing weight-bearing exercise, and assuring adequate dietary intake of calcium and vitamin D.

In an accompanying editorial, Julian Falutz from McGill University explained that the risks of antiretroviral drugs are a particularly important consideration for HIV-negative people who use them for primary prevention, since they do not get the benefits of viral suppression and reduced disease progression. But he concluded that this study indicates that Truvada appears safe to use for PrEP with benefits that outweigh the risks.

Raltegravir vs Protease Inhibitors

In a related bone study published in the May 5 advance edition of Journal of Infectious Diseases, Todd Brown from Johns Hopkins University and colleagues compared bone density changes over 96 weeks in HIV-positive people starting antiretroviral therapy (ART) for the first time. They also assessed whether levels of inflammation and immune activation biomarkers were associated with bone loss.

The 328 participants in this AIDS Clinical Trials Group study were randomly assigned to receive ritonavir-boosted atazanavir (Reyataz), ritonavir-boosted darunavir (Prezista), or raltegravir (Isentress), all with tenofovir/emtricitabine.

At week 96, the mean percentage changes in bone density were similar in the atazanavir and darunavir arms (-4.0% and -3.6% at the spine; -3.9% and -3.4% at the hip). However, bone loss was significantly greater among people using the 2 protease inhibitors combined compared with raltegravir (-3.8% vs -1.8% at the spine; -3.7% vs -2.4% at the hip).

Total body BMD decreased significantly in all treatment arms, but more so among people taking atazanavir (-2.9%) compared to those taking either darunavir (-1.6%) or raltegravir (-1.7%). The researchers suggested the differences between spine, hip, and total body BMD changes may be related to the varying composition of different types of bone.

In a multivariate analysis, higher baseline levels of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip bone loss, while markers of CD4 T-cell senescence and exhaustion (CD4+CD28-CD57+PD1+) and activation (CD4+CD38+HLA-DR+) were associated with spine bone loss.

"BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, [atazanavir/ritonavir], or [darunavir/ritonavir], but lowest among those receiving raltegravir," the researchers concluded. "Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss."

5/28/15

References

K Mulligan, DV Glidden, PL Anderson, RM Grant et al (iPrEx Study Team). Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial: DXA Results from iPrEx. Clinical Infectious Diseases. April 23, 2015 (Epub ahead of print).

J Falutz. The Bare Bones of HIV Pre-exposure Prophylaxis. Clinical Infectious Diseases. April 23, 2015 (Epub ahead of print).

TT Brown, C Moser, JS Currier, et al. Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir. Journal of Infectious Diseases. May 5, 2015 (Epub ahead of print).